Diabetes refers to a disease process derived from multiple causative factors and is characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic diseases. Therefore patients with Type II diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
Diabetes mellitus has serious effects on people's health and accompanies various complications. There are two major types of diabetes mellitus: type I diabetes mellitus characterized by little or no insulin secretory capacity due to the destruction of the pancreatic cells, and type II diabetes mellitus characterized by insulin deficiency and insulin resistance due to other causes. The prevalence of type II diabetes mellitus is 90% or more of total patients with diabetes mellitus.
The worldwide epidemic of type II diabetes has been stimulating the search for new concepts and targets for the treatment of this incurable disease. Most current therapies were developed in the absence of defined molecular, targets. Increasing knowledge on the biochemical and cellular alterations occurring in NIDDM (Non-insulin dependent diabetes mellitus) has led to the development of novel and potentially more effective therapeutic approaches to treat the disease. The role of peroxisome proliferator activated receptor in the regulation of lipid metabolism, insulin and triglycerides led to the rational design of several PPAR agonists. However, these drugs have side effects such as hypoglycemia, weight gain and the like. Accordingly, there is a strong need to develop therapeutic agents with decreased side effects, which in particular would not induce hypoglycemia and weight gain.
The other targets are: Protein Tyrosine Phosphatase 1B (PTP1B); Glycogen Synthase Kinase-3 (GSK-3); Adiponectin; Insulin Receptor Mimetic and Glucagon-like Peptidel (GLP-1).
The serine protease DPP-IV is responsible for the rapid degradation of the insulinotropic hormone GLP-1 (glucagon like peptide 1). DPP-IV inhibition results in an increase of circulating GLP-1 levels and as a consequence, improves the insulin secretion in type II diabetic patients. Other physiological effects of enhanced GLP-1 levels, such as reduction of hepatic glucose output, delayed gastric emptying and possibly an increased insulin sensitivity as well as preservation of pancreatic beta cell function, are believed to contribute to the beneficial effects (Current Topics in Medicinal Chemistry, 2007, 7, 579-595). Advantageously, since the incretins are produced by the body only when food is consumed, DPP-IV inhibition is not expected to increase the level of insulin at inappropriate times, such as between meals, which can lead to excessively low blood sugar (hypoglycemia). Inhibition of DPP-IV is therefore expected to increase insulin without increasing the risk of hypoglycemia, which is a dangerous side effect associated with the use of insulin secretagogues.
Compounds, which are inhibitors of the dipeptidyl peptidase-IV (“DPP-4”) enzyme, approved as drugs for the treatment of diabetes and particularly Type II diabetes are Sitagliptin of Merck and Vildagliptin of Novartis. To date, many candidate molecules, as DPP-IV inhibitors have been on clinical trials. A lot of research for developing DPP-IV inhibitors has been focused on molecules in which the cyano group is bonded to the pyrrolidine ring (Current Topics in Medicinal Chemistry, 2007, 7, 579-595). Representative examples of these DPP-IV inhibitors are cited in WO9819998, WO00/34241, WO04/064778, WO03/004498 and WO03/082817.
WO 2005/075426 discloses compounds of the general formula (A),
wherein Y is —S(O)m, —CH2—, CHF, or —CF2; X is NR3, O or S(O)m; m is 0, 1 or 2; the dotted line  in the carbocyclic ring represents an optional double bond (i.e., a single or double bond); R1 is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl; R2 is hydrogen, nitrile (—CN), COOH, or isosteres of carboxylic acids, including, but not limited to, SO3H, CONHOH, B(OH)2, PO3R4R5, SO2NR4R5, tetrazole, amides, esters and acid anhydrides;WO 2006/040625 discloses compounds of formula (B),
wherein Y is —S(O)n, —CH2—, CHF, or —CF2; n is 0, 1, or 2; X is a bond, C1-C5 alkyl (eg, —CH2—), or —C(═O)—; the dotted line  in the carbocyclic ring represents an optional double bond; R1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, —CN, —COOR3, CONR3R4, —OR3, —NR3R4, or NR3COR3; R2 is hydrogen, cyano, COOH, or an isostere of a carboxylic acid (such as SO3H, CONOH, B(OH)2, PO3R3R4, SO2NR3R4, tetrazole, —COOR3, —CONR3R4, NR3COR4, or —COOCOR3).WO 2007/113634 discloses compounds of formula (C),
wherein X=CH2, CHF, CF2, CHCl, CHOH, CHOCH3, NH, NCOCH3, CHPh, O, or S, Y=CN; R1 and R5 are selected from hydrogen, C1-4 alkyl and hydroxy, R2 is selected from hydrogen, C1-C4 alkyl, substituted alkyl, C1-4 alkoxy C1-4 alkyl, C1-4 hydroxyalkyl, R5NHC1-4 alkyl, and R5NHC(NH)NHC1-4 alkyl, R3 is selected from hydrogen and C1-C4 alkyl, R4 is selected from hydrogen, C1-4 alkyl, substituted alkyl, C1-C4 alkoxy, C1-C4 alkanoyloxy, hydroxy, amino, nitro, C2-C6 alkenyl, acyl and halogen, n=1 or 2, m=0, 1, or 2, R is as defined in the patent.WO 2005095339 discloses compounds of formula (D),
wherein R is R1—X—Y—(CH2)m— or R1—X—Y—(CH2)n(C(CH3)2)—, (C3-C12)cycloalkyl, optionally substituted independently with one to three hydroxy, trifluoromethyl, cyano, (C1-C3)hydroxyalkyl, (C1-C8)alkyl, or R1—X—Y—(CH2)p—, wherein p is zero, one, two, or three; R1 is heterocyclyl(C0-C8)alkyl. X is a bond, —O—, —S—, —CO—. Y is a bond or NR2.